Study Finds Biochemical Defect in Juvenile Batten Disease

For the first time, scientists studying a fatal childhood neurodegenerative disorder, juvenile Batten disease, have identified a defect in transport of the amino acid arginine in cells from affected children. The finding helps researchers understand how the disease develops and may lead to new ways of treating it.

“This is one more step toward understanding the defect in the cells that causes this disease,” says David A. Pearce, Ph.D., of the University of Rochester School of Medicine and Dentistry in New York, who led the study. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the December 1, 2005, issue of Human Molecular Genetics.*

Juvenile Batten disease results from mutations in a gene called CLN3. Symptoms of this disorder usually appear between the ages of 5 and 10 and may include seizures, mental impairment, and progressive loss of vision and motor skills. The disease is often fatal by the late teens or twenties. Juvenile Batten disease is the most common of a group of disorders called neuronal ceroid lipofuscinoses, or NCLs. NCLs are characterized by a buildup of pigments called lipofuscins in the body's cells.

The researchers studied blood cells from children with juvenile Batten disease and compared them to cells from children without the disease. They looked specifically at lysosomes, tiny sacs within the cell that contain enzymes to help to break down substances so that their components can be recycled. The lipofuscin in Batten disease accumulates within these structures.

Cells from children with the disease were unable to transport arginine across the lysosomal cell membranes as efficiently as normal cells, the researchers found. The total amount of arginine was also abnormally low in cells from affected children. Previous studies have shown that yeast cells without the yeast version of the CLN3 gene have a defect in arginine transport, but this is the first study to find a similar defect in human cells.

Blocking the function of the CLN3 gene in normal cells inhibited the transport of arginine, and tranferring normal CLN3 to Batten disease cells using gene therapy techniques restored arginine transport to normal levels, the researchers found. This showed that the arginine transport defect was caused by the gene mutation.

The researchers have not yet determined exactly how the arginine transport defect is linked to the symptoms of the disease, they say. However, arginine is one of the building blocks for protein, and maintaining a certain level of arginine may be necessary for normal cell function. Arginine also is critical for the production of nitric oxide, a molecule that is important for cell function and immune response. Nitric oxide serves as a neurotransmitter, or nerve-signaling chemical, in the nervous system. Studies have shown that either too much or too little nitric oxide in animals can increase their susceptibility to seizures. Therefore the cellular arginine deficiency may explain why children with juvenile Batten disease tend to develop epilepsy.

The researchers also found evidence that arginine deficiency may be linked to the altered pH found in cells of people with juvenile Batten disease. However, it is not yet clear whether the arginine transport defect triggers the pH abnormality, or vice versa, Dr. Pearce says.

While the results of this study provide important clues about how juvenile Batten disease causes neurodegeneration, parents of affected children should not start supplementing their children with arginine, Dr. Pearce cautions. The arginine deficiency may be the body's way of compensating for some other, yet-undetermined problem, he says. Therefore arginine supplementation could easily cause more harm than good.

The researchers are now looking at the effects of altered arginine transport in a mouse model for Batten disease in order to learn how this defect affects different cell types in the brain. They also are planning other studies to determine how CLN3 mutations lead to the arginine transport defect and how this defect affects cells. "This is our first marker for understanding what's wrong with the lysosome. It gives us something to really get our teeth into," says Dr. Pearce.

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.